Natural cell-mediated cytotoxicity of mouse and rat lymphocytes against tumors were studied in a short-term 51 Cr release assay. NK activity was strongly boosted by inoculation of viruses, immune adjuvants, interferon inducers, and by interferon itself. Interferon appears to play a central role in activating NK cells, and the in vitro effects of interferon or poly I:C could be blocked by the addition of anti-interferon. The response to poly I:C appeared to be mediated by the macrophage-dependent production of interferon, and this mechanism appears to account for the inhibitory effects of carrageenan and silica on NK activity. From studies with a variety of immunopharmocologic agents, it appeared that NK cells are derived from drug and radioresistant pre-NK cells. The differentiation from pre-NK cells to activated NK cells appeared to be independent of proliferation. The mechanism of NK activity appeared to be independent of antibody dependent cell-mediated cytotoxicity, although the levels of NK and K cell activities have correlated closely. In addition to natural cell-mediated cytotoxicity, normal mice from some strains of rats have been shown to produce migration inhibitory factor in response to some virus induced tumor cells.